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Ridaifen-F (RID-F) potently inhibits proteolytic activities of the 20S proteasome but poorly inhibits those of the 26S proteasome. Here, we report preparation of several conjugates in which various peptides are connected to RID-F. Conjugates with peptides consisting of seven amino acid residues significantly inhibited the 26S proteasome. Particularly, RID-F conjugated to an octaarginine peptide (R8, a so-called cell-penetrating peptide) inhibited intracellular proteasome activities and induced cell death in drug-resistant KMS-11 myeloma cells. RID-F conjugated to hydrophobic peptides also inhibited the 26S proteasome but failed to induce cell death, suggesting poor penetration into cells. We infer that the R8 peptide has dual functions: (1) rapid penetration of conjugates into the cell increases intracellular drug concentrations sufficient for exhibition of its effect, and (2) recognition of the conjugates by the 26S proteasome stimulates drug entry into the catalytic chamber. In the presence of ATPγS, RID-F conjugates containing R8 inhibited the 26S proteasome more potently than in the presence of ATP, suggesting efficient entry of drugs into the catalytic chamber in a similar fashion to the substrate. Taken together with docking simulations of RID-F conjugate interactions with proteasome active sites, the second function of R8 peptide is plausible. Thus, the conjugation of nonpeptidic proteasome inhibitors to a cell-penetrating peptide could represent a viable strategy for overcoming the drug-resistance of tumor cells.

We report an effective dynamic kinetic resolution (DKR) system of racemic 2-(1H-pyrrol-1-yl)alkanoic acids, which consists of a rapid racemization step via an activating substrate and an enantio-di...

Various intermediates for the synthesis of erythronolide A, an aglycon of erythromycin A, are prepared from the corresponding seco-acids using 2-methyl-6-nitrobenzoic anhydride (MNBA) in the presence of 4-(dimethylamino)pyridine (DMAP) with or without triethylamine. The efficiency of the MNBA lactonization is assessed by studying this method and comparing the results with those of the other established macrocyclization protocols. It has been finally concluded that (i) the conformationally appropriate substrate for the monomeric cyclization gave the desired lactone in excellent yield under mild reaction conditions in the presence of MNBA and DMAP, (ii) the highly-strained substrate for the cyclization also afforded the monomeric lactone in relatively good yield at 100°C in toluene, and (iii) the seco-acid having stable linear conformation, which preferred dimerizing more than forming the monomeric lactone, provided the corresponding diolide in high yield with the constant ratio of the monomer to dimeric lactone (approximately 1/5). © 2009 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 9: 305–320; 2009: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.200900017

We have developed effective methods for the total synthesis of 2-hydroxytetracosanolide and 2-hydroxy-24-oxooctacosanolide, the defensive salivary secretions of termites. The former natural product isolated from Armitermes neotenicus, a species of termite that inhabits Guyana, contains a 25-membered lactone backbone, and the latter, extracted from Pseudacanthoterme springer, an African termite, includes a 29-membered lactone moiety. The key cyclization to produce the 25- or 29-membered lactone core is performed by using 2-methyl-6-nitrobenzoic anhydride (MNBA) with a stoichiometric amount of 4-(dimethylamino)pyridine (DMAP) or a catalytic amount of 4-(dimethylamino)pyridine N-oxide (DMAPO).

A short-step route for the preparation of droloxifene has been established via the novel three-component coupling reaction among 3-pivaloyloxybenzaldehyde, cinnamyltrimethylsilane, and β-chlorophenetole, the successive installation of the side-chain part, and the base-induced migration of the double bond. The present synthesis of tetra-substituted ethylene moieties is a widely applicable strategy for producing a variety of SERMs (selective estrogen receptor modulators) and SARMs (selective androgen receptor modulators), such as tamoxifen, raloxifene, and other compounds that can lead to new drugs.

[reaction: see text] The first asymmetric total synthesis of EI-1941-1, -2, and -3, inhibitors of the interleukin-1beta converting enzyme (ICE), has been accomplished, starting from a chiral epoxy iodoquinone 11, a key intermediate in our total synthesis of epoxyquinols A and B. Despite a failure to synthesize the inhibitors by our postulated biosynthetic route, we were able to diastereoselectively synthesize them via an intramolecular carboxypalladation with the key steps being a 6-endo cyclization mode followed by beta-hydride elimination. The investigation of the biological properties of EI-1941-1, -2, and -3 and their derivatives disclosed them to be potent and effective ICE inhibitors with less cytotoxicity than EI-1941-1 and -2 in a cultured cell system.

In the proline-mediated Mannich and aldol reactions of propanal as a nucleophile, the aldimine prepared from benzaldehyde and p-anisidine is about 7 times more reactive than the corresponding alde- hyde, benzaldehyde, as an electrophile. This higher reactivity of aldimine over aldehyde is attributed to the carboxylic acid of proline protonating the basic ni- trogen atom of the aldimine more effectively than the oxygen atom of the aldehyde, an explanation which has been both experimentally and theoretically veri- fied.

[Chemical reaction: See text] The asymmetric aldol reaction of a tetra-substituted ketene silyl acetal including an alkylseleno group with aldehydes has been developed by the promotion of Sn(OTf)2 coordinated with a chiral diamine to afford the corresponding aldols having chiral quaternary centers at the alpha-positions. The facile oxidative deselenization of these aldol compounds produces optically active alpha-methylene-beta-hydroxy esters which correspond to adducts prepared by the asymmetric Morita-Baylis-Hillman reaction.

Efficient methods for the synthesis of carboxylic esters and lactones using benzoic anhydrides by the promotion of Lewis acid or basic catalyst is accounted in this paper. Various carboxylic esters are prepared in high yields through the formation of the corresponding mixed anhydrides from 4-(trifluoromethyl) benzoic anhydride (TFBA) and carboxylic acids in the presence of Lewis acid catalyst. Several macrolactones and medium-sized lactones are also prepared from the corresponding hydroxycarboxylic acids by the combined use of TFBA and an acidic species under the mild reaction conditions. Furthermore, a variety of carboxylic esters or lactones are obtained at room temperature in excellent yields with high chemoselectivities from nearly equimolar amounts of carboxylic acids and alcohols, or hydroxycarboxylic acids using 2-methyl-6-nitrobenzoic anhydride (MNBA) with basic promoters. These methods are successfully applied to the synthesis of 8-membered ring lactone moieties of cephalosporolide D, and octalactins A and B.

During screening for mammalian DNA polymerase inhibitors, we found and succeeded in isolating a potent inhibitor from a higher plant, Taxus cuspidate. The compound was unexpectedly determined to be taxinine, an intermediate of paclitaxel (taxol) metabolism. Taxinine was found to selectively inhibit DNA polymerase alpha (pol.alpha) and beta (pol.beta). We therefore, tested taxol and other derivatives and found that taxol itself had no such inhibitory effect, and only taxinine could inhibit both pol.alpha and beta. The other compounds used, one derivative, cephalomannine, and five intermediates synthesized chemically inhibited only the pol.alpha activity in vitro. None of the compounds, including taxinine, influenced the activities of the other DNA polymerases, which are reportedly targeted by many pol.beta inhibitors. With both pol.alpha and beta, all of the compounds tested noncompetitively inhibited with respect to both the DNA template-primer and the dNTP substrate.

A method for the synthesis of octalactin B is established via a new and quite effective mixed-anhydride lactonization for the synthesis of an eight-membered ring moiety using 2-methyl-6-nitrobenzoic anhydride with DMAP. Both an optically active linear precursor of the lactone and a side chain of octalactins are prepared by the enantioselective aldol reaction of ketene silyl acetals with aldehydes.

Highly diastereoselective aldol reactions of α-bromo ketones with several aldehydes were successfully carried out by using a combination of titanium(II) chloride and copper or sodium iodide in dichloromethane-pivalonitrile at low temperature. Similarly, Reformatsky reactions of α-bromo thioester with aliphatic aldehydes proceeded to afford β-hydroxy thioesters in good yields under mild conditions.

Carboxamides are prepared in high yields by dehydration condensation between nearly equimolar amounts of free carboxylic acids and amines both of which involve secondary or tertiary alkyl substituted ones with O,O'-di(2-pyridyl) thiocarbonate, a coupling reagent, in the presence of a catalytic amount of 4-(dimethylamino)pyridine.

Tamoxifen is an anticancer agent widely used for treatment of estrogen receptor (ERα)-positive breast cancer. We previously developed a novel synthesis of tamoxifen and its derivatives, named Ridaifens (RIDs). Some of them, including RID-SB8, exhibited a stronger anticancer activity than tamoxifen in ERα-positive MCF-7 cells while having lost the affinity for ERα, suggesting an ERα-independent anticancer mode of action. In this study, we investigated the underlying mechanism by which RID-SB8 exerts anticancer activity. As expected, anticancer activity of RID-SB8 was not influenced upon knockdown of ERα expression in MCF-7 cells. RID-SB8 exerted similar anticancer effects on thirteen ERα-negative cancer cell lines including human gliosarcoma SF539 cells. In SF539 cells, RID-SB8 triggered loss of mitochondrial membrane potential (ΔΨ(m)) and progression of apoptosis accompanied by activation of caspases and translocation of apoptosis-inducing factor (AIF) to the nucleus. Furthermore, it induced reactive oxygen species (ROS), and a ROS scavenger, N-acetylcysteine (NAC), canceled loss of ΔΨ(m) and progression of apoptosis triggered by RID-SB8. Using fifteen human cancer cell lines, we demonstrated a significant correlation between RID-SB8 concentration required for ROS production and that required for cytotoxic effect across these cell lines, but such correlation was not observed for tamoxifen. Finally, the selective induction of ROS and cytotoxic effect on cancer cells by RID-SB8 were confirmed. From these results, we concluded that RID-SB8 exerts an anticancer effect via a mode of action distinct from tamoxifen, and that RID-SB8 could become a promising anticancer lead compound which selectively induces ROS formation and apoptosis in cancer cells.

The anti-tumor agent, tamoxifen, is easily synthesized by the successive allylation of benzaldehyde and the Friedel–Crafts alkylation reaction of anisole with the intermediary homoallyl silyl ethers, followed by the migration of the double bond to form the desired tetra-substituted ethylenes. Several derivatives of tamoxifen are also produced according to a similar synthetic strategy.

An efficient method for the synthesis of macrolides directly from ω-hydroxycarboxylic acids is established by using 4-(trifluoromethyl)benzoic anhydride and a catalytic amount of active titanium(IV) salts together with chlorotrimethylsilane under mild conditions.

Various carboxylic esters are prepared in excellent yields from nearly equimolar amounts of free carboxylic acids and alcohols at room temperature by combined use of 4-(trifluoromethyl)benzoic anhydride and a catalytic amount of active titanium(IV) salt together with chlorotrimethylsilane.

In the presence of a catalytic amount of active titanium(IV) salt generated in situ from 1 mol of TiCl4 and 2 mol of AgOTf, weakly nucleophilic anilines react under mild conditions with nearly equimolar amounts of silyl carboxylates to afford the corresponding anilides in excellent yields using 4-(trifluoromethyl)benzoic anhydride. The mixed anhydride formed in situ from trimethylsily acetate and 4-(trifluoxomethyl)benzoic anhydride, a key intermediate of this reaction, was detected by 1H NMR experiment. Further, it was shown that the reaction of the mixed anhydrides and 2-nitroaniline was faster than that of the corresponding homo anhydrides and 2-nitroaniline.

(R)-(+)-N-Methylbenzoguanidine ((R)-NMBG) was found to function as an efficient acyl-transfer catalyst for the kinetic resolution of racemic secondary benzylic alcohols in the presence of achiral carboxylic acids and pivalic anhydride. The use of a tertiary amine in this reaction is not necessary to attain good chemical yields of the products. It was determined that diphenylacetic acid could be employed as the most suitable acyl donor for achieving a high enantioselectivity for the kinetic resolution of the racemic secondary benzylic alcohols having normal aliphatic alkyl chains at the C-1 positions. On the other hand, a less-hindered carboxylic acid, such as 3-phenylpropanoic acid, functioned as a better acyl donor for the kinetic resolution of racemic secondary benzylic alcohols having branched aliphatic alkyl chains at the C-1 positions.

In the presence of a catalytic amount of Lewis acid, various carboxylic esters or S-phenyl carbothioates are prepared in excellent yields by the respective reactions of equimolar amounts of silyl carboxylates and alkyl silyl ethers or phenyl silyl sulfides with 4-trifluoromethylbenzoic anhydride.

The lactonization of silyl ω-siloxycarboxylates is successfully carried out under mild conditions in good to high yields by using p-trifluoromethylbenzoic anhydride and a catalytic amount of active acidic species generated in situ from TiCl4 and AgClO4.

Highly diastereo- and enantioselective aldol-type reactions of a silyl enol ether with aldehydes including aromatic, aliphatic, and α,β-unsaturated ones are performed in propionitrile (solvent) by the use of a catalytic amount of chiral tin(II) Lewis acid consisting of tin(II) triflate and a chiral diamine. The asymmetric environments created by the chiral catalysts in the enantioselective aldol reaction are discussed by employing five kinds of chiral diamines.

Three types of sugars, 6-deoxy-L-tallose,4-C-methyl-D-ribose, and D-ribose were synthesized from both achiral starting materials, α,β-unsaturated aldehydes and silyl enol ethers of α-benzyloxy thioesters, by successive asymmetric aldol and vicinal dihydroxylation reactions.

In the presence of a catalytic amount of Lewis acid, various carboxylic esters or S-phenyl carbothioates are prepared in excellent yields by the respective reactions of equimolar amounts of silyl carboxylates and alkyl silyl ethers or phenyl silyl sulfides with 4-trifluoromethylbenzoic anhydride.

In the presence of a catalytic amount of titanium(IV) salt, various S-phenyl carbothioates are prepared in excellent yields by the reaction of nearly equimolar amounts of silyl derivatives of carboxylic acids and benzenethiols with p-trifluoromethylbenzoic anhydride.

Various carboxylic esters are prepared in excellent yields from nearly equimolar amounts of free carboxylic acids and alcohols at room temperature by combined use of 4-(trifluoromethyl)benzoic anhydride and a catalytic amount of active titanium(IV) salt together with chlorotrimethylsilane.

In the presence of a catalytic amount of active titanium(IV) salt generated in situ from 1 mol of TiCl4 and 2 mol of AgOTf, weakly nucleophilic anilines react under mild conditions with nearly equimolar amounts of silyl carboxylates to afford the corresponding anilides in excellent yields using 4-(trifluoromethyl)benzoic anhydride. The mixed anhydride formed in situ from trimethylsily acetate and 4-(trifluoxomethyl)benzoic anhydride, a key intermediate of this reaction, was detected by 1H NMR experiment. Further, it was shown that the reaction of the mixed anhydrides and 2-nitroaniline was faster than that of the corresponding homo anhydrides and 2-nitroaniline.

Catalytic Diels-Alder reactions between several 1,3-dienes and α,β-unsaturated ketones are effectively promoted by the combined use of diphenyltin sulfide (Ph2Sn=S) and silver perchlorate or Lawesson’s reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide) and silver perchlorate under mild conditions.

1-t-Butyldimethylsiloxy-8,11,11-trimethylbicyclo[5.3.1]undec-7-en-9-one (2) has been synthesized via intramolecular aldol condensation of the precursor 3 by combined use of lithium diisopropylamide (LDA) and CeCl3. The dicarbonyl compound 3 was prepared by allylation of 8-membered ring ketone 6b.

Optically active 3,7-dibenzyloxy-4,8-di-t-butyldimethylsiloxy-5,5-dimethyl-6-p-methoxybenzyloxy-2-octanone (2) has been synthesized by way of diastereoselective aldol reaction between 4-benzyloxy-5-t-butyldimethylsiloxy-2,2-dimethyl-3-p-methoxy-benzyloxypentanal (3) and ketene silyl acetal 4 using MgBr2·OEt2 as a catalyst. The chiral pentanal 3 was synthesized either by asymmetric aldol reaction of both prochiral aldehyde 5 and ketene silyl acetal 4 using a chiral Lewis acid or by diastereoselective aldol reaction between the chiral aldehyde 6 derived from L-serine and the lithium enolate derived from methyl isobutyrate.

An efficient method for the synthesis of (−)-cephalosporolide D was established via successive enantioselective aldol reaction and effective construction of 8-membered ring lactone moiety.

Highly diastereoselective aldol reaction of α-bromo ketones with aliphatic aldehydes was successfully carried out by using titanium(II) chloride and copper in dichloromethane at low temperature. Similarly, Reformatsky-type reaction of α-bromo thioester with aliphatic aldehydes was promoted under mild conditions to afford β-hydroxy thioesters in good to moderate yields.

Various intermediates for the synthesis of erythronolide A, an aglycon of erythromycin A, are prepared from the corresponding seco-acids using 2-methyl-6-nitrobenzoic anhydride (MNBA) in the presence of 4-(dimethylamino)pyridine (DMAP) with or without triethylamine. The efficiency of the MNBA lactonization is assessed by studying this method and comparing the results with those of the other established macrocyclization protocols. It has been finally concluded that (i) the conformationally appropriate substrate for the monomeric cyclization gave the desired lactone in excellent yield under mild reaction conditions in the presence of MNBA and DMAP, (ii) the highly-strained substrate for the cyclization also afforded the monomeric lactone in relatively good yield at 100°C in toluene, and (iii) the seco-acid having stable linear conformation, which preferred dimerizing more than forming the monomeric lactone, provided the corresponding diolide in high yield with the constant ratio of the monomer to dimeric lactone (approximately 1/5). © 2009 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 9: 305–320; 2009: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.200900017

Unsymmetrical alkyl 2-hydroxy-1-(1-hydroxyalkyl)alkyl ketones (bis-aldols) are successfully synthesized by way of sequential two aldol reactions using α-bromo ketones and two different aldehydes. In the first reaction, α-bromo-β-stannyloxy ketones are formed by tin(II) trifluoromethanesulfornate-promoted aldol reaction of α-bromo ketones with several aldehydes. Bis-aldols are then formed via the second aldol reaction between another aldehydes and dianionic enolates generated by the reduction of α-bromo-β-metalloxy ketones with titanium(IV) iodide and copper.

In the presence of a catalytic amount of titanium(IV) salt, various S-phenyl carbothioates are prepared in excellent yields by the reaction of nearly equimolar amounts of silyl derivatives of carboxylic acids and benzenethiols with p-trifluoromethylbenzoic anhydride.

Various carboxylic esters are obtained at room temperature in excellent yields with high chemoselectivities from nearly equimolar amounts of carboxylic acids and alcohols using 2,6-dimethyl-4-nitrobenzoic anhydride with triethylamine by the promotion of 4-(dimethylamino)pyridine. The efficiency of the esterification is compared to those of other dehydrations using substituted benzoic anhydrides as coupling reagents. This method was successfully applied to the synthesis of threo-aleuritic acid lactone and the desired 17-membered ring compound was prepared in high yield at room temperature from the corresponding free trihydroxycarboxylic acid using 2,6-dimethyl-4-nitrobenzoic anhydride in the presence of 4-(dimethylamino)pyridine.

syn-α,β-Dihydroxy thioesters are prepared in good yields with high diastereo- and enantioselectivities by the asymmetric aldol reaction of 1-trimethylsiloxy-1-ethylthio-2-t-butyldimethylsiloxyethene with aldehydes using a chiral promoter consisting of tin(II) triflate, a chiral diamine and dibutyltin diacetate.

In the presence of a chiral promoter consisting of tin(II) triflate, a chiral diamine, and tributylin fluoride, the silyl enol ether of S-ethyl ethanethioate or S-tert-butyl ethanetioate reacts with aldehydes to afford the corresponding aldol-type adducts in good yields with high enantioselectivities. In the reaction of silyl enol ether of S-ethyl propanethioate with aldehydes, perfect stereochemical control is attained by the combined use of tin(II) triflate, a chiral diamine, and dibutylin diacetate. A wide variety of aldehydes, including aliphatic, α,β-unsaturated, and aromatic aldehydes, are applicable to this reaction. The chiral promoters are characterized by 119 Sn NMR spectra and proved to form the three-component complexes, which behave as chiral Lewis acids. The reaction proceeds directly from silyl enol ethers without any accompanying metal exchange on the enolates

Various carboxamides or peptides were synthesized from the corresponding carboxylic acids and amines or alpha-amino acids in high yields by the catalysis of 4-(dimethylamino)pyridine N-oxide (DMAPO) with 2-methyl-6-nitrobenzoic anhydride (MNBA). Because the segment-coupling reaction of alpha-amino acids proceeds through the effective activation of the carboxylic acid moieties with DMAPO in the presence of tertiary amines under mild conditions, undesired racemization was hardly observed in the synthesis of oligopeptides such as Z-Gly-Phe-Val-OMe, Z-Phe-Val-Ala-OMe, and Bz-Val-Val-OMe.

Anti-α,β-dihydroxy thioesters are prepared with excellent enantioselectivities by the asymmetric aldol reaction between both achiral aldehydes and silyl enol ethers derived from α-benzyloxy thioesters in the presence of a chiral promoter consisted of chiral diamine coordinated tin(II) triflate and dibutyltindiacetate.

Two new synthetic pathways to the anti-cancer agent tamoxifen and its derivatives were developed. The first route involved the aldol reaction of benzyl phenyl ketone with acetaldehyde followed by Friedel-Crafts substitution with anisole in the presence of Cl(2)Si(OTf)(2) to produce 1,1,2-triaryl-3-acetoxybutane, a precursor of the tamoxifen derivatives. The second one utilized the novel three-component coupling reaction among aromatic aldehydes, cinnamyltrimethylsilane, and aromatic nucleophiles using HfCl(4) as a Lewis acid catalyst to produce 3,4,4-triarylbutene, that is also a valuable intermediate of the tamoxifen derivatives. The former strategy requires a total of 10 steps from the aldol formation to the final conversion to tamoxifen, whereas the latter needs only three or four steps to produce tamoxifen and droloxifene including the installation of the side-chain moiety and the base-induced double-bond migration to form the tetra-substituted olefin structure. This synthetic strategy seems to serve as a new and practical pathway to prepare not only the tamoxifen derivatives but also the other SERMs (selective estrogen receptor modulators) including estrogen-dependent breast cancer and osteoporosis agents.

[Structure: see text] The total synthesis of pseudo 2-epibotcinolide (1b) through several featured synthetic approaches has been attained. First, the chiral linear precursors of the nine-membered ring compound is stereoselectively constructed by the asymmetric aldol reaction for producing beta-hydroxy ester units. Second, the key cyclization reaction to form the nine-membered lactone moiety is efficiently achieved by the extremely facile and powerful mixed-anhydride method promoted by 2-methyl-6-nitrobenzoic anhydride (MNBA) with basic promoters.

[structure: see text] An effective method for the total synthesis of 2-hydroxy-24-oxooctacosanolide, a defensive salivary secretion of the African termite Pseudacanthotermes spiniger, has been developed. The key lactonization to form a 29-membered ring lactone core is performed using 2-methyl-6-nitrobenzoic anhydride with a catalytic amount of 4-(dimethylamino)pyridine N-oxide.

Octalactin A, an antitumor agent containing an eight-membered lactone moiety, has been stereoselectively prepared by means of enantioselective aldol reactions of selected silyl enolates with achiral aldehydes, promoted by a chiral Sn(II) complex. The medium-sized lactone part was effectively constructed by way of a new and rapid mixed-anhydride lactonization using 2-methyl-6-nitrobenzoic anhydride (MNBA) with a catalytic amount of 4-(dimethylamino)pyridine (DMAP) or 4-(dimethylamino)pyridine 1-oxide (DMAPO). The use of only 5 mol % of DMAP or 2 mol % of DMAPO rapidly promoted formation of the medium-sized ring of the octalactin, demonstrating the remarkable efficiency of the new lactonization protocol.

Various carboxylic esters are obtained at room temperature in excellent yields with high chemoselectivities from nearly equimolar amounts of carboxylic acids and alcohols using 2-methyl-6-nitrobenzoic anhydride with triethylamine by the promotion of a basic catalyst such as 4-(dimethylamino)pyridine. A variety of lactones are also prepared in high yields at room temperature from the corresponding omega-hydroxycarboxylic acids with use of 2-methyl-6-nitrobenzoic anhydride in the presence of 4-(dimethylamino)pyridine. A similar reaction occurs with triethylamine when using a catalytic amount of 4-(dimethylamino)pyridine 1-oxide as an effective promoter for the intramolecular condensation reaction. These methods are successfully applied to the synthesis of erythro-aleuritic acid lactone and an eight-membered-ring lactone moiety of octalactins A and B. The efficiency of the cyclizations is compared to those of other reported lactonizations.

An efficient mixed-anhydride method for the synthesis of carboxylic esters and lactones using benzoic anhydride having electron withdrawing substituent(s) is developed by the promotion of Lewis acid catalysts. In the presence of a catalytic amount of TiCl2(ClO4)2, various carboxylic esters are prepared in high yields through the formation of the corresponding mixed-anhydrides from 3,5-bis(trifluoromethyl)benzoic anhydride and carboxylic acids. The combined catalyst consisting of TiCl2(ClO4)2 together with chlorotrimethylsilane functions as an effective catalyst for the synthesis of carboxylic esters from free carboxylic acids and alcohols with 4-(trifluoromethyl)benzoic anhydride. Various macrolactones are prepared from the free ω-hydroxycarboxylic acids by the combined use of 4-(trifluoromethyl)benzoic anhydride and titanium(IV) catalysts together with chlorotrimethylsilane under mild reaction conditions. The lactonization of trimethylsilyl ω-(trimethylsiloxy)carboxylates using 4-(trifluoromethyl)benzoic anhydride is also promoted at room temperature in the presence of a catalytic amount of TiCl2(ClO4)2. An 8-membered ring lactone, a synthetic intermediate of cephalosporolide D, is successfully synthesized according to this mixed-anhydride method using 4-(trifluoromethyl)benzoic anhydride by the promotion of a catalytic amount of Hf(OTf)4.

An oxidative dimerization reaction, involving the three successive steps of oxidation, 6 pi-electrocyclization, and Diels-Alder reaction, has been experimentally and theoretically investigated for the three 2-alkenyl-3-hydroxymethyl-2-cyclohexen-1-one derivatives epoxyquinol 3, epoxyquinone 6, and cyclohexenone 10. Of the sixteen possible modes of the oxidation/6 pi-electrocylization/Diels-Alder reaction cascade for the epoxyquinone 6, and eight for the cyclohexenone 10, only the endo-anti(epoxide)-anti(Me)-hetero and endo-anti(Me)-hetero modes are, respectively, observed, while both endo-anti(epoxide)-anti(Me)-hetero and exo-anti(epoxide)-anti(Me)-homo reaction modes occur with the epoxyquinol 3. Intermolecular hydrogen-bonding is found to be the key cause of formation of both epoxyquinols A and B with 3, although epoxyquinone 6 and cyclohexenone 10 both gave selectively only the epoxyquinol A-type product. In the dimerization of epoxyquinol 3, two monomer 2H-pyrans 5 interact with each other to afford intermediate complex 28 or 29 stabilized by hydrogen-bonding, from which Diels-Alder reaction proceeds. Theoretical calculations have also revealed the differences in the reaction profiles of epoxyquinone 6 and cyclohexenone 10. Namely, the rate-determining step of the former is the Diels-Alder reaction, while that of the latter is the 6 pi-electrocyclization.